BACKGROUND The homozygous K108E mutation of interferon regulatory factor 8 (IRF8) is reported to cause dendritic cell (DC) and monocyte deficiency. However, more widespread immune dysfunction is predicted from the multiple roles ascribed to IRF8 in immune cell development and function. OBJECTIVE We sought to describe the effect on hematopoiesis and immunity of the compound heterozygous R83C/R291Q mutation of IRF8, which is present in a patient with recurrent viral infection, granuloproliferation, and intracerebral calcification. METHODS Variant IRF8 alleles were identified by means of exome sequencing, and their function was tested by using reporter assays. The cellular phenotype was studied in detail by using flow cytometry, functional immunologic assay transcriptional profiling, and antigen receptor profiling. RESULTS Both mutations affected conserved residues, and R291Q is orthologous to R294, which is mutated in the BXH2 IRF8-deficient mouse. R83C showed reduced nuclear translocation, and neither mutant was able to regulate the Ets/IRF composite element or interferon-stimulated response element, whereas R291Q retained BATF/JUN interactions. DC deficiency and monocytopenia were observed in blood, dermis, and lung lavage fluid. Granulocytes were consistently increased, dysplastic, and hypofunctional. Natural killer cell development and maturation were arrested. TH1, TH17, and CD8+ memory T-cell differentiation was significantly reduced, and T cells did not express CXCR3. B-cell development was impaired, with fewer memory cells, reduced class-switching, and lower frequency and complexity of somatic hypermutation. Cell-specific gene expression was widely disturbed in interferon- and IRF8-regulated transcripts. CONCLUSIONS This analysis defines the clinical features of human biallelic IRF8 deficiency, revealing a complex immunodeficiency syndrome caused by DC and monocyte deficiency combined with widespread immune dysregulation.

中文翻译：

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双等位干扰素调节因子 8 突变：一种复杂的免疫缺陷综合征，伴有树突状细胞缺陷、单核细胞减少和免疫失调。


背景 据报道，干扰素调节因子 8 (IRF8) 的纯合 K108E 突变会导致树突状细胞 (DC) 和单核细胞缺陷。然而，IRF8 在免疫细胞发育和功能中的多重作用预计会导致更广泛的免疫功能障碍。目的 我们试图描述 IRF8 复合杂合 R83C/R291Q 突变对造血和免疫的影响，该突变存在于患有复发性病毒感染、颗粒增殖和脑内钙化的患者中。方法 通过外显子组测序鉴定变体 IRF8 等位基因，并通过报告基因分析测试其功能。通过使用流式细胞术、功能免疫分析转录谱和抗原受体谱对细胞表型进行了详细研究。结果两种突变均影响保守残基，R291Q 与 R294 是直系同源的，R294 在 BXH2 IRF8 缺陷小鼠中发生突变。 R83C 显示核易位减少，并且两种突变体都无法调节 Ets/IRF 复合元件或干扰素刺激的反应元件，而 R291Q 保留 BATF/JUN 相互作用。在血液、真皮和肺灌洗液中观察到 DC 缺乏和单核细胞减少。粒细胞持续增加、发育不良和功能减退。自然杀伤细胞的发育和成熟被抑制。 TH1、TH17 和 CD8+ 记忆 T 细胞分化显着降低，并且 T 细胞不表达 CXCR3。 B 细胞发育受损，记忆细胞减少，类别转换减少，体细胞超突变的频率和复杂性降低。干扰素和 IRF8 调节的转录本中的细胞特异性基因表达受到广泛干扰。 结论 该分析定义了人类双等位基因 IRF8 缺陷的临床特征，揭示了由 DC 和单核细胞缺陷以及广泛的免疫失调引起的复杂免疫缺陷综合征。